1. Field of Invention
This invention relates generally to non-pharmacologic adjunct (add-on) treatment for Dementia, more specifically to adjunct treatment of Dementia including Alzheimer's disease by modulating electrical signals to a selected nerve or nerve bundle utilizing an easily implanted lead-receiver and an external stimulator.
2. Background
There is mounting scientific evidence that electrical stimulation has beneficial therapeutic effects for patients with Dementia and probable Alzheimer's disease. Most of the scientific studies are performed utilizing the technique of transcutaneous electrical nerve stimulation (TENS). In the TENS method (such as a device manufactured by Xytron Medical), two standard carbon rubber electrodes with gel are fixed on patient's skin across the tissue to be stimulated, one electrode being the negative pole and other being the positive pole. Utilizing the two electrodes, asymmetric biphasic pulses are used for stimulation with varying frequency and pulse widths. Because the skin has high impedance, relatively large outputs are required to stimulate, and the site to be stimulated is not very specific. Other tissues including muscle, between the two skin electrodes will be stimulated.
Another method of stimulating nerve is to use a percutaneous needle, or a lead with one end (distal end) being next to the nerve and utilizing a patch somewhere on the skin as the return electrode. Such a method is not feasible for long term stimulation because of the potential for infection, but can be useful for short term testing.
Two recent studies reported by Scherder et al., using TENS as the method of stimulation, described the benefits on memory and affective behavior in patients with probable Alzheimer's disease. There was a partial disappearance of the treatment effects on memory and affective behavior after a treatment-free period of 6 weeks, suggesting that continuation of the stimulation is necessary for maintaining or even further improving the treatment effects.
The rationale underlying the TENS study was that peripheral nerve stimulation would activate the hippocampus and hypothalamus structures which are affected in Alzheimer's disease (AD). This assumption is based upon animal experimental studies in which hippocampal activity was found to increase after peripheral tactile stimulation and the activity of the hypothalamus was enhanced by electro-acupuncture, a type of peripheral electrical stimulation. The hippocampus is highly involved in memory processes, in close association with other brain regions such as the inferomedial temporal cortex and the ventromedial prefrontal cortex. The hypothalamus plays a crucial role in affective behavior in Alzheimer's disease.
Most nerves in the human body are composed of thousands of fibers, of different sizes designated by groups A, B and C, which carry signals to and from the brain. The vagus nerve, for example, may have approximately 100,000 fibers of the three different types, each carrying signals. Each axon (fiber) of that nerve conducts only in one direction, in normal circumstances. The A and B fibers are myelinated (i.e., have a myelin sheath, constituting a substance largely composed of fat), whereas the C fibers are unmyelinated.
A commonly used nomenclature for peripheral nerve fibers, using Roman and Greek letters, is given in the table below,
External Conduction Diameter Velocity Group (.mu.m) (m/sec) Myelinated Fibers A.alpha. or IA 12-20 70-120 A.beta.: IB 10-15 60-80 II 5-15 30-80 A.gamma. 3-8 15-40 A.delta. or III 3-8 10-30 B 1-3 5-15 Unmyelinted fibers C or IV 0.2-1.5 0.5-2.5
The diameters of group A and group B fibers include the thicknesses of the myelin sheaths. Group A is further subdivided into alpha, beta, gamma, and delta fibers in decreasing order of size. There is some overlapping of the diameters of the A, B, and C groups because physiological properties, especially the form of the action potential, are taken into consideration when defining the groups. The smallest fibers (group C) are unmyelinated and have the slowest conduction rate, whereas the myelinted fibers of group B and group A exhibit rates of conduction that progressively increase with diameter. Group B fibers are not present in the nerves of the limbs, they occur in white rami and some cranial nerves. Myelinated fibers also have very low stimulation thresholds compared to the unmyelinated type, and exhibit a particular strength-duration curve or respond to a specific pulse width versus amplitude for stimulation. The A and B fibers can be stimulated with relatively narrow pulse widths, from 50 to 200 microseconds (.mu.s), for example. The A fiber conducts slightly faster than the B fiber and has a slightly lower threshold. The C fibers are very small, conduct electrical signals very slowly, and have high stimulation thresholds typically requiring a wider pulse width (300-1,000 .mu.s) and a higher amplitude for activation. Selective stimulation of only A and B fibers is readily accomplished. The requirement of a larger and wider pulse to stimulate the C fibers, however, makes selective stimulation of only C fibers, to the exclusion of the A and B fibers, virtually, unachievable inasmuch as the large signal will tend to activate the A and B fibers to some extent as well.
A-Beta fibers respond very well to high frequency stimulation, e.g., 100 Hz with an intensity just above threshold. In a recent study, A-Beta fibers also appeared to respond to low-frequency stimulation (2 Hz) with a higher intensity. Activation of A-Delta and C fibers is usually caused by low-frequency stimulation (less than 10 Hz) with higher intensity. To activate all three types of afferent nerve fibers, high-frequency and low-frequency stimulation can be combined in one treatment.
The vagus nerve is composed of somatic and visceral afferents (i.e., inward conducting nerve fibers which convey impulses toward the brain) and efferents (i.e., outward conducting nerve fibers which convey impulses to an effector). Usually, nerve stimulation activates signals in both directions (bi-directionally). It is possible, however, through the use of special electrodes and waveforms, to selectively stimulate a nerve in one direction only (unidirectionally). The vast majority of vagal nerve fibers are C fibers, and a majority are visceral afferents having cell bodies lying in masses or ganglia in the skull. The central projections terminate largely in the nucleus of the solitary tract which sends fibers to various regions of the brain, e.g., the hypothalamus, hippocampus, and amygdala. See FIG. 1 (from: Epilepsia, vol. 31, suppl. 2: 1990, page S2).
An activation of higher-level areas, e.g. the hippocampus and hypothalamus, by TENS or cranial nerve (such as vagal nerve) stimulation might be transmitted by afferent nerve fibers, i.e. thick-myelinated A-Beta fibers, thin-myelinated A-Delta fibers, and Unmyelinated C fibers. The basic premise of vagal nerve stimulation is that vagal visceral afferents have a diffuse central nervous system (CNS) projection, and activation of these pathways has a widespread effect on neuronal excitability.
Observations on the profound effect of electrical stimulation of the vagus nerve on central nervous system (CNS) activity, extends back to 1930's. Intermittent vagal stimulation has been relatively safe and well tolerated. The minimal side effects of tingling sensations and brief voice abnormalities have not been distressing. The vagus nerve provides an easily accessible, peripheral route to modulate central nervous system (CNS) function. Other cranial nerves can be used for the same purpose, but the vagus nerve is preferred because of its easy accessibility. In the human body there are two vagal nerves (VN), the right VN and the left VN. Each vagus nerve is encased in the carotid sheath along with the carotid artery and jugular vein. The innervation of the right and left vagal nerves is different. The innervation of the right vagus nerve is such that stimulating it results in profound bradycardia (slowing of the heart rate). The left vagal nerve has some innervation to the heart, but mostly innervates the visceral organs such as the gastrointestinal tract. It is known that stimulation of the left vagal nerve does not cause any significant deleterious side effects.
The cervical component of the vagus nerve (10.sup.th cranial nerve) transmits primarily sensory information that is important in the regulation of autonomic activity by the parasympathetic system. General visceral afferents constitute approximately 80% of the fibers of the nerve, and thus it is not surprising that vagal stimulation (VS) can profoundly affect CNS activity. With cell bodies in the nodose ganglion, these afferents originate from receptors in the heart, aorta, lungs, and gastrointestinal system and project primarily to the nucleus of the solitary tract which extends throughout the length of the medulla oblongata
U.S. Pat. No. 3,796,221 (Hagfors) is directed to controlling the amplitude, duration and frequency of electrical stimulation applied from an externally located transmitter to an implanted receiver by inductively coupling. Electrical circuitry is schematically illustrated for compensating for the variability in the amplitude of the electrical signal available to the receiver because of the shifting of the relative positions of the transmitter-receiver pair. By highlighting the difficulty of delivering consistent pulses, this patent points away from applications such as the current application, where consistent therapy may need to be continuously sustained over a prolonged period of time. The methodology disclosed is focused on circuitry within the receiver, which would not be sufficient when the transmitting coil and receiving coil assume significantly different orientation, which is likely in the current application. The present invention discloses a novel approach for this problem, using "targets" located in the external patch electrode. Additionally, the mode of stimulation in Hagfors patent is "bipolar" whereas in the current patent, the mode of stimulation is "unipolar" i.e. between the tip electrode and case.
U.S. Pat. No. 5,269,303 (Wernicke) is directed to the use of pacemaker technology (an implantable pulse generator) for the treatment of dementia. The pacemaker technology concept consists of a stimulating lead which is connected to a pulse generator (containing the circuity and DC power source) implanted subcutaneously or submuscularly, somewhere in the pectoral or axillary region, with a personal computer (PC) based programmer being external. Once the patient is programmed, the fully functional circuity and power source being fully implanted within the patients body. In such a system when the battery is depleted, the whole pulse generator (circuitry and power source) is disconnected from the permanently implanted lead and replaced in a surgical procedure. This patent neither anticipates practical problems of an inductively coupled system for adjunct therapy of dementia, nor suggest solutions to the same for an inductively coupled system for adjunct therapy of dementia.
U.S. Pat. No. 4,867,164 (Zabara) generally discloses animal research and experimentation related to epilepsy and the like, and use of pacemaker technology (an implantable pulse generator) for the stimulation of vagus nerve. Some of the key hypothesis on which the patent is based upon, have since been shown to be incorrect.
U.S. Pat. No. 5,540,734 (Zabara) is directed to stimulation of one or both of a patient's trigeminal and glossopharyngeal nerve utilizing an implanted pulse generator.
U.S. Pat. No. 5,031,618 (Mullett) discloses a position sensor for chronically implanted neuro stimulator for stimulating the spinal cord. The position sensor, located in a chronically implanted programmable spinal cord stimulator, modulates the stimulation signals depending on whether the patient is erect or supine.
U.S. Pat. No. 4,573,481 (Bullara) is directed to an implantable helical electrode assembly configured to fit around a nerve. The individual flexible ribbon electrodes are each partially embedded in a portion of the peripheral surface of a helically formed dielectric support matrix.
U.S. Pat. No. 3,760,812 (Timm et al.) discloses nerve stimulation electrodes that include a pair of parallel spaced apart helically wound conductors maintained in this configuration.
U.S. Pat. No. 4,979,511 (Terry) discloses a flexible, helical electrode structure with an improved connector for attaching the lead wires to the nerve bundle to minimize damage.
An implantable pulse generator and lead with a PC based external programmer is advantageous for cardiac pacing applications for several reasons, including:
1) A cardiac pacemaker needs to sense the intrinsic activity of the heart, because in vast majority of instances, the cardiac pacemakers deliver electrical output only during the brief periods when patients either have pauses in their intrinsic cardiac activity or during those periods of time when the heart rate drops (bradycardia) below a certain pre-programmed level. Therefore, for most of the time, in majority of patients, the cardiac pacemaker "sits" quietly monitoring the patient's intrinsic cardiac activity. PA1 2) The stimulation frequency for cardiac pacing is typically close to 1 Hz as opposed to approximately 20 Hz or higher, typically used in nerve stimulation applications. PA1 3) Majority of patients that require cardiac pacemaker support are typically in 60's, 70's or 80's years in age. PA1 1) The hardware components implanted in the body are much less. This is advantageous for the patient in terms of patient comfort, and it decreases the chances of the hardware getting infected in the body. Typically, when an implantable system gets infected in the body, it cannot be easily treated with antibiotics and eventually the whole implanted system has to be explanted. PA1 2) Because the power source is external, the physician can use stimulation sequences that are more effective and more demanding on the power supply such as longer "on" time. PA1 3) The external inductively-coupled nerve stimulation (EINS) system is quicker and easier to implant. PA1 4) The external pulse generator does not need to be monitored for "End-of-Life" EOL like the implantable system, thus resulting in cost saving and convenience. PA1 5) The inductively-coupled nerve stimulation (EINS) system can be manufactured at a significantly lower cost than an implantable pulse generator and programmer system, providing the patient and medical establishment with cost effective therapies. PA1 6) The EINS system makes it more convenient for the patient or caretaker to turn the device on. PA1 7) Occasionally, an individual responds adversely to a medical device and the implanted hardware must be removed. In such a case, a patient having the EINS system has less implanted hardware to be removed and the cost of pulse generator does not become a factor.
The combined effect of these three factors is that the pacemaker can have a battery life of 10-15 years, and for most patients in whom a pacemaker is indicated are implanted only once, with perhaps one surgical pulse generator replacement.
For nerve stimulation applications, the stimulation frequency is typically 20 Hz or higher, and the total stimulation time per day is much longer, which results in battery expenditure that is typically much higher than for cardiac pacemakers, and the battery will not last nearly as long. The impact of surgical generator replacement and expense will become significant, and detract from the appeal of this therapy. There are several other advantages of the present inductively coupled system as set forth below,
In the conventional manner of implanting, a cervical incision is made above the clavicle, and another infraclavicular incision is made in the deltapectoral region for the implantable stimulus generator pocket. To tunnel the lead to the cervical incision, a shunt-passing tool is passed from the cervical incision to the generator pocket, where the electrode is attached to the shunt-passing tool and the electrode is then "pulled" back to the cervical incision for attachment to the nerve. This standard technique has the disadvantage that it is time consuming and it tends to create an open space in the subcutaneous tissue. Post surgically the body will fill up this space with serous fluid, which can be undesirable.
To make the subcutaneous tunneling simpler and to avoid possible complication, one form of the implantable lead body is designed with a hollow lumen to aid in implanting. In this embodiment, a special tunneling tool slides into a hollow lumen. After the cervical and infraclavicular incisions are made, the tunneling tool and lead are simply "pushed" to the cervical incision and the tunneling tool is pulled out. Since the tunneling tool is inside the lead, no extra subcutaneous space is created around the lead, as the lead is pushed. This promotes better healing post-surgically.
The apparatus and methods disclosed herein also may be appropriate for the treatment of other conditions, as disclosed in co-pending applications filed on Oct. 26, 1998, entitled APPARATUS AND METHOD FOR ADJUNCT (ADD-ON) THERAPY OF PARTIAL COMPLEX EPILEPSY, GENERALIZED EPILEPSY AND INVOLUNTARY MOVEMENT DISORDERS UTILIZING AN EXTERNAL STIMULATOR, now U.S. Pat. No. 6,205,359, and APPARATUS AND METHOD FOR ADJUNCT (ADD-ON) THERAPY FOR PAIN SYNDROMES UTILIZING AN IMPLANTABLE LEAD AND AN EXTERNAL STIMULATOR, now U.S. Pat. No. 6,208,902, the disclosures of which are incorporated herein by reference.